Non-insulin-dependent diabetes mellitus (NIDDM) is a major health problem affecting approximately 14 million Americans. It causes significant morbidity and mortality and imposes a great economic burden as the annual cost of diabetes currently exceeds $20 billion. Moreover, the socioeconomic effects of NIDDM are expected to escalate with the increase in its prevalence due to aging of the American society and rapid growth of minority populations at high risk for the disease. Since most of the morbidity and mortality of NIDDM arise from its long-term complication, prevention and early detection of the disease should have a tremendous human, social, and economic impact. The major aim of this proposal is to test the hypothesis that intervention can prevent or delay the decompensation from impaired glucose tolerance (IGT) to NIDDM and the progression to fasting hyperglycemia in normoglycemic newly diagnosed NIDDM and possibly reduce the incidence of atherosclerotic cardiovascular (ASCVD). As part of the multicenter NIDDM primary prevention trial (DK- 93-07), we plan to study 200 obese (body mass index greater than or equal to 27kg/m2) subjects (100 whites, and 100 blacks) aged 40-65 years with persistent IGT or newly diagnosed NIDDM (with fasting normoglycemia) according to the World Health Organization criteria. They will be recruited from the population of Los Angeles served by Southern California Kaiser Permanente Foundation on the basis of fasting plasma glucose concentration measured during their routine health care. The proposed intervention is a 2x2 factorial design with one factor being a special low-fat diet and exercise program versus usual care and the second factor being a drug that improves insulin sensitivity (e.g., the biguanide metformin) versus placebo. The primary endpoints will be the development of NIDDM for subjects with IGT and worsening to fasting hyperglycemia for those with newly diagnosed NIDDM. The secondary endpoints will be changes in blood pressure, the concentrations of lipids, lipoproteins, fibrinogen, ad plasminogen activator inhibitor 1, and the development of ASCVD as assessed from the clinical data, the ankle/arm ratio, and the electrocardiogram. The success of this trial will have a great impact in alleviating human suffering and decreasing the socioeconomic effects of NIDDM.